WO2010103550A2

WO2010103550A2 - Process for the preparation of intermediates

Info

Publication number: WO2010103550A2
Application number: PCT/IN2010/000148
Authority: WO
Inventors: Ketan Dhansukhlal Vyas; Vidyadhar Kashinath Jadhav; Manish Shridhar Tamhankar; Nitin Hanumant Gaikwad; Vinayak Shrikant Ekbote; Sharad Vishnu Sonawane; Aditi Milind Panandikar
Original assignee: Indoco Remedies Limited
Priority date: 2009-03-13
Filing date: 2010-03-12
Publication date: 2010-09-16
Also published as: WO2010103550A3

Abstract

An improved process for the preparation of (5)-3,4-dihydro-6- chloro-4-hydroxy-2-(3- methoxypropyl)-4H-thieno[3,2-e]-l,2-thiazine 1,1 -dioxide of Formula (I) is disclosed.

Description

"PROCESS FOR THE PREPARATION OF INTERMEDIATES"

FIELD OF INVENTION:

The present invention relates to an improved process for the preparation of (S) - 3, 4 - dihydro - 6 - chloro - 4 - hydroxyl - 2 - (3 - methoxypropyl) - 4H- thieno [3, 2-e] 1, 2 - thiazine 1, 1 - dioxide of Formula - 1

Formula - 1

BACKGROUND OF THE INVENTION:

The compound (S) - 3, 4 - dihydro - 6 - chloro - 4 - hydroxyl - 2 - (3 - methoxypropyl) - 4H- thieno [3, 2-e] 1, 2 - thiazine 1, 1 - dioxide of Formula - I is a key intermediate for the synthesis of Brinzolamide used as a carbonic anhydrase inhibitor for controlling intraocular pressure associated with glaucoma.

The carbonic anhydrase inhibitor described above is disclosed in US patent No. 5,378,703, which discloses a process for preparing the racemic modification of the compound which after resolution yields the compound Brinzolamide.

US patent No. 5,344,929 describes the synthesis of (S) - 3, 4 - dihydro - 6 - chloro - 4 - hydroxyl - 2 - (3 - methoxypropyl) - 4H- thieno [3, 2-e] 1 , 2 - thiazine 1 , 1 - dioxide of Formula - I starting from 3-acetyl-2,5-dichlorothiophene (Formula - II). The process involves preparation of thioether 3-acetyl-5-chloro-2-(benzylthio)thiophene (Formula - III) by reacting 3-acetyl-2,5-dichlorothiophene (Formula - II) with thiourea and benzyl chloride in presence of ethanol and sodium hydroxide solution as base. The benzylthio group of the compound of Formula - III is converted into sulfonamide group by either carrying out oxidative chlorination using chlorine gas in dilute aqueous acetic acid / hydrochloric acid followed by treatment with ammonium hydroxide or by bubbling chlorine gas into solution of thioether in ethyl acetate, treating the intermediate sulfenyl chloride with ammonia gas to get the intermediate sulfenamide (Formula - IV), which on oxidation with hydrogen peroxide in the presence of sodium tungstate dihydrate yields 3- acetyl-5-chloro-2-thiophenesulfonamide (Formula - V). Bromination of the compound of Formula - V in ethyl acetate using pyridinium bromide perbromide in presence of sulfuric acid forms 3-bromoacetyl-5-chloro-2-thiophenesulfonamide (Formula - VI) which is triturated with solvent to limit the dibromo impurity less than 10%. Asymmetric reduction of the compound of Formula -VI in methyl tert - butyl ether using (+)-β- chlorodiisopinocamphenylborane results in chiral intermediate (S) - 3 - (2 - bromo 1 - hydroxyethyl) - 2 - thiophenesulfonamide (Formula - VII), which on cyclisation with aqueous sodium hydroxide yields (S)-3,4-dihydro-6-chloro-4-hydroxy-4H-thieno[3,2-e]- 1,2-thiazine 1,1 -dioxide (Formula - VIII). Alkylation of the compound of Formula - VIII with l-bromo-3-methoxypropane in the presence of potassium carbonate and dimethylsulfoxide results in the required compound (S) - 3, 4 - dihydro - 6 - chloro - 4 - hydroxyl - 2 - (3 - methoxypropyl) - 4H- thieno [3, 2-e] 1 , 2 - thiazine 1, 1 - dioxide of Formula - 1.

Scheme - 1

Formula - III

Formula - II

Formula - VI Formula - IV

Formula - V

Formula - VII Formula - 1

Formula - VIII The drawbacks of the invention are;

^■ requires excess ammonium hydroxide for neutralizing acetic acid or hydrochloric acid after oxidative chlorination increasing load of ammonium salts in effluent treatment plant;

^■ use of explosive reagent hydrogen peroxide for oxidation ;

^■ use of costly sodium tungstate as catalyst for oxidation results in sludge formation which is difficult to dispose off makes the process environmentally unsafe;

^■ use of expensive,unstable,hygroscopic pyridinium bromide perbromide for bromination results in the formation of undesired dibromo impurity;

^■ requires trituration to limit the dibromo impurity less than 10%;

^■ requires resolution of the racemic modification of the compound of Formula - 1 to get the desired isomer.

US patent No. 5,470,973 describes another process for the preparation of racemic modification of the intermediate compound (S) - 3, 4 - dihydro - 6 - chloro - A - hydroxyl - 2 - (3 - methoxypropyl) - 4H- thieno [3, 2-e] 1, 2 - thiazine 1, 1 - dioxide of Formula - I, starting from 3-bromoacetyl-5-chloro-2-thiophenesulfonamide (Formula - VI) as per the reaction sequence shown in Scheme - 2 below;

Scheme - 2:

Formula - VI Formula - VlI Formula - VIlI

Formula - IX

Formula - 1

The process involves reduction of 3 - bromoacetyl - 5 - chloro - 2 - thiophenesulfonamide (Formula - VI) with sodium borohydride resulting in formation of bromohydrin intermediate (Formula - VII), which on cyclisation with sodium hydroxide yields 3,4 - dihydro - 6 - chloro - 4 - hydroxyl - 4H-thieno[3,2-e]-l,2-thiazine 1, 1 - dioxide (Formula - VIII). Alkylation of the compound of Formula - VIII with l-bromo-3- methoxypropane in the presence of potassium carbonate and dimethylsulfoxide results in racemic modification of the compound of Formula - I. The 4-hydroxy group of racemic compound is further oxidized with sodium dichromate and sulfuric acid which results in the intermediate 6 - chloro - 2 - (3 - methoxypropyl) - 2,3 - dihydro - 4H - thieno[3,2- e][l,2]thiazin - 4 - one 1,1 - dioxide (Formula - IX). The compound of Formula - IX on asymmetric reduction using borane - tetrahydrofiiran complex and catalytic amount of oxazaborol results in the required intermediate compound (S) - 3, 4 - dihydro - 6 - chloro - 4 - hydroxyl - 2 - (3 - methoxypropyl) - 4H- thieno [3, 2-e] 1, 2 - thiazine 1, 1 - dioxide of Formula - 1.

The drawbacks of the invention are;

■ involves reduction of the keto group once to form racemic alcohol and then oxidation of the hydroxyl group to get keto group reintroduced in the cyclic compound, which on asymmetric reduction yields the required isomer resulting in the increased number of steps;and

^■ use of costly reagent borane tetrahydrofuran complex with oxazaborol catalyst that renders the process industrially uneconomical.

Therefore, there remains a need for an improved process for preparing the intermediate (S) - 3, 4 - dihydro - 6 - chloro - 4 - hydroxy - 2 - (3 - methoxypropyl) - 4H- thieno [3, 2-e] 1, 2 - thiazine 1,1 - dioxide of Formula - I that eliminates or substantially reduces the impurities, decreases the number of steps, and employs a more robust process which is industrial friendly and economical.

Thus the present inventors have come out with a process which ameliorates the problems in the prior art with the use of stable and less costlier reagents which are industrially safe to handle and does not generate the sludge, which makes the process rigid and environmentally safe.

Objectives of the invention:

The main objective of the present invention is to provide an improved process to prepare the intermediate compound (S) - 3, 4 - dihydro - 6 - chloro - 4 - hydroxyl - 2 - (3 - methoxypropyl) - 4H- thieno [3, 2-e] 1, 2 - thiazine 1, 1 - dioxide of Formula - 1;

Another objective of the present invention is to prepare the intermediate compound of Formula - 1 with the use of easily available, stable and cost effective reagents. Summary of the invention:

The present invention provides a process for preparation of the compound (S)-3,4- dihydro-6-chloro-4-hydroxyl-2-(3-methoxypropyl)-2H-thieno[3,2-e]-l,2-thiazinel,l- dioxideof Formula - 1;

Formula - 1 Comprising of; i) carrying out oxidative chlorination of compound 3-acetyl-5-chloro-2- (benzylthio) thiophene of Formula - III to get intermediate sulfonyl chloride (Formula - X), followed by in situ reaction with ammonium hydroxide solution to get sulfonamide compound of Formula - V.

Formula - X Formula - V

ii) bromination of the compound of Formula - V with brominating reagent in solvent to get the compound 3-bromoacetyl-5-chloro-2-thiophenesulfonamide of Formula - VI;

Formula - Vl iii) reducing the compound of Formula - VI using chiral reducing agent to form the compound (S)-3 - (2 - bromo 1 - hydroxyethyl) - 2 - thiophenesulfonamide of Formula - VII; followed by cyclisation of compound of Formula - VII in presence of base to isolate compound (S)-3,4-dihydro-6- chloro-4-hydroxy-4H-thieno[3,2-e]-l,2-thiazine 1,1 -dioxide (Formula - VIII);

Formula - VII Formula - VIII

iv) reacting the compound of Formula - VIII with 1 -bromo-3-methoxypropane to isolate (S)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyl)-4H- thieno[3,2-e]-l,2-thiazine 1,1-dioxide of Formula - I.

Description of the invention:

The present invention provides an improved process to prepare the compound (S)-3,4- dihydro-6-chloro-4-hydrόxy-2-(3-methoxypropyl)-4H-thieno[3,2-e]- 1 ,2-thiazine 1 ,1- dioxide of Formula - I. Further the present invention overcomes the inherent difficulties that exist in prior art when it is desirable to produce the intermediate on commercial scale.

Specifically the problems in the prior art, such as, the use of hydrogen peroxide in presence of sodium tungstate for oxidation, use of unstable, hygroscopic pyridinium bromide perbromide in presence of sulphuric acid and ethyl acetate for bromination that results in the formation of undesired dibromo derivative up to 10% and use of dimethyl sulfoxide an expensive solvent for alkylation are completely avoided in the present invention. The present invention utilizes liquid bromine and trimethyl borate as a brominating agent followed by isolating the brominated product from water thereby reducing the dibromo impurity to less than 3% thus making the process robust, rigid and commercially viable. The reaction sequence is represented by the scheme - 3 below; Scheme - 3:

Formula - X Formula - V

Formula - VI

Formula - VIII Formula - VII

Formula - 1

Accordingly, in one of the embodiment of the present invention the compound 3-acetyl-5- chloro-2-(benzylthio) thiophene of Formula - III is subjected to oxidative chlorination by bubbling chlorine gas in presence of solvent mixture ethyl acetate and water. The ratio of ethyl acetate and water used is in the range of 90: 10 to 96: 4. The compound 3-acetyl-5- chloro-2-(benzylthio) thiophene was dissolved in ethyl acetate : water mixture and stirred, maintaining the temperature in the range of -5°C to 10⁰C, passed chlorine gas till complete consumption of the starting material. The reaction mass is then cooled to O⁰C. Aqueous ammonia solution is added to the reaction solution maintaining the temperature in the range of 0 to 20⁰C until pH of the reaction mass is in the range of 9 - 10. The mixture is stirred and the solvent distilled out under reduced pressure maintaining temperature below 60⁰C. To the residual mass charged 1 : 1 mixture of cyclohexane and water and stirred at 25 - 30⁰C for about 1.0 hour. The solid mass is filtered and dried to get 3-acetyl-5-chloro-2-thiophenesulfonamide (Formula - V).

In another embodiment of the present invention the compound of Formula - V is subjected to bromination using brominating agent in presence of solvent selected from Ci - C₄ linear or branched chain alcohols and aliphatic esters either single or mixture thereof. The brominating agent used is selected from dibromo dimethylhydantoin, N - bromosuccinimide, sodium bromide with oxone, liquid bromine with trimethylborate and liquid bromine. The preferred brominating agent used for bromination is dibromo dimethylhydantoin, liquid bromine with trimethylborate and liquid bromine, wherein the most preferred brominating agent used is liquid bromine with trimethylborate and dibromo dimethylhydantoin. The C] - C₄ linear or branched chain alcoholic solvent is selected from methanol, ethanol, propanol, butanol, isopropanol, sec - butanol and ten. butanol; wherein the preferred solvent used is methanol. The aliphatic esters which are used as solvents include ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate; wherein the preferred solvent used is ethyl acetate. To the compound of Formula - V in methanol trimethylborate is added with constant stirring and cooled to 0 - 5°C. Bromine is then added slowly to the reaction mass maintaining temperature at 0 - 10⁰C. After complete addition, the mixture was stirred further for 1.0 hour and raised the temperature slowly to attain 25 - 35°C. Saturated solution of sodium hydrogen sulfite is added to the reaction mass to destroy any excess of free bromine. The solvent is distilled out completely under vacuum maintaining temperature below 40⁰C. Water is then added to the residual mass and acidified to pH = 1 with dilute sulphuric acid. The temperature of the reaction mass is raised to 50⁰C and maintained at 50 - 60⁰C for 2 .0 hours. The mixture is cooled to 20 - 3O⁰C and filtered to get the solid mass of 3-bromoacetyl-5- chloro-2-thiophenesulfonamide of Formula - VI.

By carrying out bromination using the present invention, inventors are able to control the contamination of dibromo impurity in the isolated product to less than 3.0% as compared to 10% or more reported in the prior art.

The compound of Formula - VI is subjected to asymmetric reduction using (+)-β- chlorodiisopinocamphenylborane at temperature of -30 to 0⁰C in presence of solvent methyl tert - butyl ether using the known prior art process to isolate (S) - 3 - (2 - bromo 1 - hydroxyethyl) - 2 - thiophenesulfonamide of Formula - VII.

After completion of the reduction reaction, charged aqueous solution of sodium hydroxide and the mixture is stirred for 2 - 3 hours at a temperature in the range of 20 - 30⁰C to accomplish complete cyclisation. The product is isolated by phase separation, and acidifying the aqueous phase to pH of 1 - 2 using dilute hydrochloric acid followed by extraction with ethyl acetate and distillation of the solvent to get the residual mass which is crystallized using toluene to isolate (S)-3,4-dihydro-6-chloro-4-hydroxy-2H-thieno[3,2- e]-l,2-thiazine 1,1 -dioxide (Formula - VIII).

In another embodiment of the present invention the compound of Formula - VIII is subjected to N - alkylation with 1 - bromo - 3 - methoxypropane in presence of base and catalyst. The reaction is carried out in presence of solvent acetone. The preferred base used in the alkylation reaction is anhydrous potassium carbonate. The catalyst used in the reaction is selected from N, N - dimethylformamide, dimethyl sulfoxide and potassium iodide; wherein the preferred catalyst used is potassium iodide. The reaction is carried out by taking the compound of Formula - VIII in acetone to which the catalyst and base are added with constant stirring. Alkylating reagent 1 - bromo - 3 - methoxypropane is added and heated to reflux and maintained there for 12 - 15 hours monitoring the completion of the reaction on TLC. After the completion of the reaction, the reaction mass is cooled to 25 - 3O⁰C and filtered. The solvent is distilled out completely and, after this, water is added to the residual mass and extracted with ethyl acetate. The organic layer is washed with dilute sodium hydroxide solution and dried over anhydrous sodium sulfate. The solvent is distilled out completely under reduced pressure below 40⁰C to get the light yellow mass of compound (S)-3,4-dihydro-6-chloro-4-hydroxy-2-(3- methoxypropyl)-4H-thieno[3,2-e]-l,2-thiazinel,l-dioxide of Formula - 1.

The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respect as illustrative and non restrictive to the invention. Examples:

Example 1: Preparation of 3 - Acetyl - 5 - chloro - 2 - (benzylthio) thiophene:

Thiourea (107.50 gm) and benzyl chloride (161.50 gm) charged in a premixed solution of isopropyl alcohol (1125 ml) and water (375 ml). Raised the temperature to reflux under stirring and maintained for 2.0 hours. Cooled the reaction mixture to 6O⁰C and further charged with 3 - acetyl - 2, 5 - dichlorothiophene (250 gm) followed by addition of 4M sodium hydroxide solution (770 ml) maintaining at 60 - 65°C. The mixture was again brought to reflux and maintained for 3.0 hours. Cooled the reaction mixture to 25 - 30⁰C and further stirred with 2.25% sodium hypochlorite solution (250 ml) for 30 minutes. The solid mass obtained after filtration was washed with water followed by isopropyl alcohol, and dried at 5O⁰C to get the product 3 - acetyl - 5 - chloro - 2 - (benzylthio) thiophene till constant weight.

Yield = 354 gm % yield = 98%

Example 2: Preparation of 3- Acetyl -5 - chloro - 2 - thiophenesulfonamide:

Charged 3 - acetyl - 5 - chloro - 2 - (benzylthio) thiophene (200 gm) in mixture of ethyl acetate: water (4.40 ltr) and cooled under stirring to 0 - 5°C. The chlorine gas was bubbled under stirring maintaining the temperature range and monitoring the reaction on TLC for completion. After completion of the reaction, charged slowly ammonium hydroxide solution (500 ml). Reaction mixture was then stirred for 30 min. at 0-5⁰C and monitored for completion on TLC. Solvent was distilled out under reduced pressure below 60⁰C till complete removal of ethyl acetate. 1 : 1 mixture of water and cyclohexane (800 ml) was then added to the reaction mixture and stirred at 25 - 30°C for 1 hour. The solid obtained after filtration was washed with water followed by cyclohexane and then dried at 50⁰C to get 3-acetyl-5-chloro-2-thiophenesulfonamide till constant weight.

Yield = 116.38 gm % yield = 68.5% Example 3: Preparation of 3 - Bromoacetyl - 5 - chloro - 2 - thiophenesulfonamide:

Charged trimethylborate (125 ml) in premixed solution of 3-acetyl-5-chloro-2- thiophenesulfonamide (100 gm) and methanol (800 ml) at 25 - 30⁰C and stirred for 10 minutes. Cooled the reaction mixture to 0 - 5°C followed by slow addition of bromine (32.30 ml) maintaining the temperature at 0 - 10⁰C. Reaction mixture was stirred at 0 - 10⁰C for 1 hour. Further raised the temperature of the reaction slowly to 25 - 3O⁰C and maintained under constant stirring for 17 - 20 hours. Charged aqueous 20% sodium hydrogen sulfite solution (100 ml) to the reaction mixture and stirred at 25 - 30⁰C for 30 minutes. Distilled out methanol completely under vacuum below 40⁰C. Charged Water (700 ml) followed by 4M sulfuric acid solution (50 ml) to the reaction mixture and raised the temperature of the reaction mixture to 50 - 55°C and maintained for 1.5 hours. Cooled the reaction mixture to 25 - 30⁰C. Filtered the product 3 - bromoacetyl - 5 - chloro - 2 - thiophenesulfonamide, washed with water till neutral pH. Dried the product at 50⁰C till constant weight. Yield = 127.0 gm % yield = 95.5%

Example - 4: 3-Bromoacetyl-5-chloro-2-thiophenesulfonamide:

Charged 3-acetyl-5-chloro-2-thiophenesulfonamide (100 gm) to the premixed reaction solution of dibromo dimethylhydantoin (70.44 gm) and ethyl acetate (5.00 Itr) at 20 - 30⁰C, maintained under stirring for one hour. Cooled the reaction mixture to 0 - 5°C followed by addition of cone, sulfuric acid (100 ml) maintaining temperature at 0 - 5⁰C under stirring for 1 hour. The temperature is gradually raised to 20 - 25°C and maintained for 15 -18 hours, while monitoring the reaction for completion on HPLC. After completion of reaction charged water (2.5 lit.) and stirred, separated the organic layer and washed with brine solution (4x 1.0 lit.). Organic layer separated and dried over anhydrous sodium sulfate. Filtered and concentrated the solvent under reduced pressure below 5O⁰C to get pale yellow colored solid residue. Charged methylene chloride (300 ml) at 25 - 30⁰C and stirred for 1 hour and cooled to 15 - 2O⁰C. Maintained for 1 h and filtered, washed with cold methylene chloride (2x75 ml). Dried the compound 3 - bromoacetyl - 5 - chloro - 2 - thiophenesulfonamide at 25 - 35°C till constant weight. Yield = 125.0 gm % yield = 94 .0 %

Example 5: (S) - 3 , 4 - Dihydro - 6 -chloro - 4 - hydroxyl - 4H- thieno[3,2-e] -1,2 - thiazine 1,1 - dioxide:

Charged under stirring 3 - bromoacetyl - 5 - chloro - 2 - thiophenesulfonamide (40 gm) in methyl tert-butylether (MTBE) (720 ml). Cooled the reaction mixture to - 30⁰C and charged solution of (+)-β-chlorodiisopinocamphenylborane in hexane (140 ml) under nitrogen atmosphere. Maintained at -25 to -20⁰C for 1.5 hour. The reaction mixture was then warmed to -20 to -15⁰C and charged cooled solution of 1 M aqueous sodium hydroxide (520 ml). The temperature of the reaction mixture was raised to 25 - 3O⁰C and stirred vigorously for 2 hours. The separated aqueous layer was then acidified to pΗ = 1 using 12 M hydrochloric acid solution. The aqueous layer was further extracted twice with ethyl acetate (2x225 ml each). The combined ethyl acetate extracts was washed with brine and dried over anhydrous sodium sulfate. Filtered the inorganic salt and concentrated the filtrate. Charged toluene (80 ml) and stirred at 25 - 3O⁰C for 1.0 hour. Filtered the product and washed with toluene (50 ml) and methylene chloride (30 ml). Dried the compound (S)-3,4-dihydro-6-chloro-4-hydroxy-4Η-thieno[3,2-e]-l,2-thiazine- 1,1-dioxide in air at 25 - 35°C till constant weight.

Yield = 25.1 gm % yield = 80%

Example 6: (S)-3, 4 - Dihydro - 6 - chloro - 4 - hydroxyl - 2 - (3 - methoxypropyl) - 4H- thieno [3, 2-e] - 1, 2 - thiazine 1, 1 - dioxide:

Charged 1 - bromo - 3 - methoxypropane (3.83 gm) in the suspension of (5)-3, 4- dihydro-6-chloro-4-hydroxy-4Η-thieno [3,2-e]-l,2-thiazine- 1,1 -dioxide (5.0 gm), potassium carbonate (5.77 gm) and potassium iodide (0.69 gm) in acetone (35 ml). Raised the temperature of the reaction mixture to 53-56°C and maintained for 12-15 hours at reflux. Reaction was monitored by TLC. After completion of the reaction, cooled the reaction mixture to 25 - 30⁰C and filtered. The residue was washed with acetone (25 ml). Filtrate was concentrated under vacuum, charged water (50 ml) to the residue and extracted with ethyl acetate (2><50 ml).Combined the ethyl acetate extracts and washed with 1 M aqueous sodium hydroxide (25 ml) solution, followed by washing with sodium hypochlorite solution (20 ml). Dried over anhydrous sodium sulfate, filtered, and concentrated the solvent to get light-yellow coloured oil of (S)-3,4-dihydro-6-chloro-4- hydroxy-2-(3-methoxypropyl)-4H-thieno [3,2-e]-l,2-thiazine 1,1 -dioxide.

Yield = 5.50 gm % yield = 85%

Example 7: (S)-3, 4-Dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyI)-4Η-thieno- [3,2-e]-l,2-thiazine 1,1-dioxide:

Charged 1-bromomethoxy propane (57.5 gm) to the suspension of (iS)-3,4-Dihydro-6- chloro-4-hydroxy-4H-thieno[3,2-e]-l,2-thiazine-l,l-dioxide (75.0 gm) and potassium carbonate (86.3 gm) in dimethylsulfoxide (375 ml) at RT. Raised the temperature of the reaction mixture to 50°-55°C and maintained for 4-5 hours at 50 - 55°C. Reaction was monitored by TLC. After completion of reaction charged water (2250 ml) at 25 - 3O⁰C. Reaction mixture was then extracted with ethyl acetate, (3><525 ml). All ethyl acetate layers were combined and washed with IN Sodium hydroxide solution (375 ml), sodium hypochlorite solution, 2.2% (300 ml) and brine solution, (3><225 ml). Ethyl acetate layer then dried over anhydrous sodium sulfate (62 gm), filtered and concentrated under vacuum at 45°C. Finally apply high vacuum for 2-3 hr to isolate get light-yellow coloured oil of (5)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyl)-4H-thieno [3,2-e]-l,2- thiazine 1,1-dioxide constant weight.

Yield = 79.O g % yield = 80.98%

Claims

We claim,

1. A process for preparation of the compound (5)-3,4-dihydro-6- chloro-4-hydroxy- 2-(3- methoxypropyl)-4H-thieno[3, 2-e]-l,2-thiazine 1,1 -dioxide of Formula-I;

Formula-I Comprising of; i) carrying out oxidative chlorination of compound 3-acetyl-5-chloro-2- (benzylthio) thiophene of Formula-Ill to get intermediate sulfonyl chloride (Formula-X),

Formula - X ii) reacting the compound of Formula - X with ammonium hydroxide solution to get sulfonamide compound of Formula - V.

Formula - V iii) bromination of the compound of Formula-V with brominating reagent in presence of solvent to get the compound 3-bromoacetyl-5-chloro-2- thiophenesulfonamide of Formula-VI;

Formula - VI iv) reducing the compound of Formula- VI using chiral reducing agent to form the compound (S)-3-(2-bromo l-hydroxyethyl)-2-thiophenesulfonarnide of Formula-VII; followed by cyclisation of compound of Formula-VII in presence of base to isolate compound (5)-3,4-dihydro-6-chloro-4-hydroxy- 4H-thieno[3,2-e]-l,2-thiazine 1,1-dioxide (Formula-VIII); and

Formula - VII Formula - VIII v) reacting the compound of Formula-VIII with l-bromo-3-methoxypropane to isolate (S)-3,4-dihydro-6-chloro-4-hydroxy-2-(3-methoxypropyl)-4H- thieno[3,2-e]-l,2-thiazine 1,1-dioxide of Formula-I.

2. The process according to claim 1, wherein step (i) oxidative chlorination carried out using chlorine gas in presence of solvent mixture comprising ethyl acetate and water.

3. The process according to claim 2, wherein the ratio of ethyl acetate and water is 90: 10 to 96: 4.

4. The process according to claim 1, wherein the brominating agent in step (iii) is selected from dibromo dimethylhydantoin, N-bromosuccinimide, sodium bromide with oxone, liquid bromine with trimethylborate and liquid bromine.

5. The process according to claim 1 step (iii), wherein the solvent used in bromination is selected from Ci - C₄ linear or branched chain alcohols and aliphatic esters either single or mixture thereof .

6. The process according to claim 5, wherein Ci - C₄ linear or branched chain alcoholic solvent is selected from methanol, ethanol, propanol, butanol, isopropanol, sec-butanol and ten. Butanol.

7. The process according to claim 5, wherein the aliphatic esters which include ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate.

8. The process according to claim 1, wherein the step (v) is carried out in presence of a base and catalyst.

9. The process according to claim 8, wherein the base is anhydrous potassium carbonate.

10. The process according to claim 8, wherein the catalyst is selected from N, N- dimethylformamide, dimethyl sulfoxide and potassium iodide.